Copper overload is observed in various human conditions including cholestatic disorders, chronic ingestion of copper contaminated water, and in Wilson's disease. Similar conditions exist in veterinary medicine, including the susceptibility of sheep and various breeds of dogs, such as the Bedlington Terrier, to copper accumulation.
Wilson's disease is a genetic disorder that affects about one in 50,000 to 100,000 people worldwide. The disorder is due to abnormal changes (mutations) in a gene that is inherited as an autosomal recessive trait. The disease gene responsible for Wilson's disease, known as the ATP7B gene, is located on the long arm (q) of chromosome 13 (13q14.3). The protein encoded by this gene plays a role in the transport of copper (copper-transporting ATPase).
Wilson's disease, commonly known as hepatolenticular degeneration is a systemic disorder of copper metabolism. Patients with this disease suffer from copper accumulation in the liver. The liver eventually becomes overburdened from excessive copper storage and ultimately copper is released from the liver into other organs, particularly, the brain, eyes and the kidneys. Accumulation of copper in the liver causes acute or chronic inflammation of the liver (hepatitis) or severe liver disease due to progressive loss of liver function (cirrhosis). Common symptoms of copper accumulation in the liver include loss of appetite (anorexia), fatigue, weakness/weight loss, abdominal swelling/yellowish discoloration of the skin and eyes (jaundice). This disorder may also cause enlargement of the liver (hepatomegaly), spleen (splenomegaly) or in some cases, both (hepatosplenomegaly).
Neurologic disorders persist in individuals suffering from Wilson's disease. Neurologic symptoms include tremor of the head, arms/legs, slowness of movements (bradykinesia), particularly, those of the tongue, lips and jaw. Patients with Wilson's disease suffer from psychiatric problems. These symptoms include increasing agitation, irritability, drastic mood swings, depression accompanied by bizarre behaviors.
Therapy in individuals with copper overload pathologies such as Wilson's disease aims at efficacious removal of excessive copper from the body to prevent ongoing copper accumulation and deposition. This means that drug therapy must be continued throughout life. Lack of treatment or disruption of drug therapy often results in life threatening complications or irreversible organ damage. Current therapy for copper accumulation utilizes the chelating agent, D-penicillamine. D-penicillamine reduces copper toxicity by binding to copper in the body, making it water-soluble so it can be excreted in the urine.
Because D-penicillamine is a hydrolytic product of penicillin, it has been associated with the induction of hypersensitivity reactions. D-penicillamine reduces the amount of copper in the body, but it does not affect the increased levels of reactive oxygen species caused by the copper.
Reactive oxygen species and reactive nitrogen species (ROS/RNS), such as hydroxyl (OH.), peroxyl radicals (ROO.), superoxide anion (O2.) and the peroxy nitrite anion (NO.), are constantly produced as a result of metabolic reactions in living systems. RNS and ROS that are associated with an increased amount of copper in the body attack critical biomolecules, such as lipids, proteins, nucleic acids, and the unsaturated fatty acids of biomembranes. These attacks result in lipid peroxidation and consequently cause the destruction of proteins and DNA. Various disorders and diseases in humans/animals such as cancers, brain disorders, platelet aggregation and atherosclerosis are associated with elevated levels of ROS/RNS.
Antioxidants are scavenging agents that typically react with ROS/RNS and effectively interrupt the propagation of new free radical species. While in vitro studies have shown that potent antioxidants protect against the oxidative stress induced by increased copper levels, the usefulness of antioxidants in copper toxicosis therapy is not well known. Therefore, a continuing need exists for effective therapies for copper overload conditions such as Wilson's disease.